The aim of this renewal grant application is to obtain new marine natural products with activity against solid tumors which are insensitive to most of the known anticancer drugs, Attention continues on the natural products from sponges and sponge-derived fungi in an ongoing collaboration between the Natural Products group at U. of California Santa Cruz lead by Prof. Crews and the Experimental Therapeutics Program at the Henry Ford Cancer Center lead by Prof. Valeriote. The aims for the next grant period are: #1 .To discover new bioactive, small biomolecules (MW 400-1000) obtained from sponges by using the in vitro mammalian cell assay of Aim 3 to: (a) Expand the structural-diversity potential of our sponge extract library through annual expeditions to sites of high biodiversity, (b) Broaden the chemodiversity of extracts by collections from different geographical regions of the same sponge species that may be rich in bacterial populations. (c) Focus on 300 extracts & compounds per year to select for agents with "cellular selectivity" for solid tumors insensitive to conventional anticancer agents. #2.To discover new active small biomolecules 'MW 400-1000) from sponge-derived fungi cultured in saltwater by using the cell assay of Aim 3 to: (a) sharpen the selection of taxa for the annual investigation of 100 strains that produce novel compounds by employing chemistry dereplication results, assessing for uniqueness of taxonomy, and exploding salt-obligate characteristics. (b) Focus on fungal cultures derived from deepwater environments; and (c) Apply the idea of "One Strain Many Compounds" to broaden the chemistry obtained from active cultures. #3.To employ the unique in vitro disk diffusion assay as a primary screen to identify extracts with solid tumor selectivity for fractionation in Aim 5. #4.To continue work on leads obtained from prior research involving solid tumor selective and/or potent cytotoxic extracts. #5.To efficiently isolate and characterize in vitro solid tumor selective active compounds by bioassay-guided isolation of active hits identified in Aims 1,2, and 3. #6. To complete the isolation of compounds from active extracts and elucidate their entire structures. #7. To engage in pharmacology studies on compounds by: (a) defining their in vitro clonogenic concentration-survival characteristics, and (b) Completing pharmacokinetic studies. #8. To obtain patent coverage for important new active compounds by developing supporting data.